Robinson, D.P., Hall, O.J., Nilles, T.L., Bream, J.H., and Klein, S.L. (2014). 17β-estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs. Journal of Virology. Vol. 88:9 p. 4711-4720. http://jvi.asm.org/content/88/9/4711.long
Influenza viruses cause contagious respiratory illness with a sudden onset of high fever, cough, sore throat, runny or stuffy nose, body aches, headache, and fatigue. There are 3 types of influenza viruses (A, B, and C) with influenza A and B viruses causing seasonal epidemics of disease. The Centers for Disease Control (CDC) estimates that flu-associated deaths range from 3000-49,000 each year depending on length and severity of the season (see the CDC website for more general information about the flu virus, http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm). Moreover, pulmonary inflammatory diseases such as influenza are known to differentially affect males and females with women suffering a worse outcome. Prior evidence indicates that estrogen impacts the function of various immune cells and therefore may contribute to the differential outcomes between men and women following respiratory infections. The authors of this paper aimed to examine the role of estradiol (E2, one of the 2 major biologically active estrogens in non-pregnant humans) in both the host response to the influenza A virus (IAV) and the ability of IAV to replicate in the host. It was hypothesized that estradiol alters the recruitment and activity of immune cells therefore affecting the outcome of IAV infection. In order to test this hypothesis, female C57BL/6 mice were ovariectomized and implanted with either E2 or placebo capsules followed by infection with IAV. E2 treatment resulted in less morbidity as compared to placebo-treated females. E2 did not affect virus replication, but increased the levels of chemokines in lung homogenates, increased recruitment of neutrophils to the lungs, and increased the levels of interferon-γ and tumor necrosis factor-α released from virus-specific CD8 T cells. These effects were dependent on neutrophils because depletion of neutrophils in females treated with E2 increased morbidity, reduced chemokine production, and reduced CD8 T cell IFN-g production. In summary, sustained E2 levels affect the host response to IAV infection through a neutrophil-dependent mechanism leading to improved outcomes. This work sets the stage for further mechanistic studies related to how E2 regulates these effects and supports the consideration of E2 levels in the treatment of IAV infected patients.